Submissions for variant NM_000090.4(COL3A1):c.4295G>T (p.Arg1432Leu)

gnomAD frequency: 0.00001  dbSNP: rs772428340

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000475974	SCV000541792	uncertain significance	Ehlers-Danlos syndrome, type 4	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 1432 of the COL3A1 protein (p.Arg1432Leu). This variant is present in population databases (rs772428340, gnomAD 0.004%). This missense change has been observed in individuals with clinical features of Ehlers-Danlos syndrome (PMID: 25846194, 33125268; Invitae). ClinVar contains an entry for this variant (Variation ID: 404289). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt COL3A1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV001188122	SCV001355095	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-03-30	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with leucine at codon 1432 of the COL3A1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with two siblings with Ehlers-Danlos-like symptoms without the vascular impairments typical of vascular Ehlers-Danlos (PMID: 25846194, 31075413) and in one individual affected with spontaneous coronary artery dissection (PMID: 33125268). This variant has been identified in 5/251334 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV001574625	SCV001801479	uncertain significance	not provided	2022-06-09	criteria provided, single submitter	clinical testing	Identified in two siblings, one with features consistent with classical EDS (cEDS) and one with features of hypermobile EDS (hEDS) (Stembridge et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); Not located in the triple helical region, where the majority of pathogenic missense variants occur (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(R1265L); This variant is associated with the following publications: (PMID: 34318601, 25846194, 33125268)
Ambry Genetics	RCV001188122	SCV002629582	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-11-04	criteria provided, single submitter	clinical testing	The p.R1432L variant (also known as c.4295G>T), located in coding exon 51 of the COL3A1 gene, results from a G to T substitution at nucleotide position 4295. The arginine at codon 1432 is replaced by leucine, an amino acid with dissimilar properties. This variant was detected in a proband and sibling with features of Ehlers-Danlos syndrome (EDS), but who were not reported to have arterial or organ fragility findings associated with vascular EDS (Stembridge NS et al. Am. J. Med. Genet. A, 2015 Aug;167A:1763-72). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002480343	SCV002776850	uncertain significance	Ehlers-Danlos syndrome, type 4; Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome	2021-08-09	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000475974	SCV004828275	uncertain significance	Ehlers-Danlos syndrome, type 4	2024-05-14	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with leucine at codon 1432 of the COL3A1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with two siblings with Ehlers-Danlos-like symptoms without the vascular impairments typical of vascular Ehlers-Danlos (PMID: 25846194, 31075413) and in one individual affected with spontaneous coronary artery dissection (PMID: 33125268). This variant has been identified in 5/251334 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GenomeConnect, ClinGen	RCV000475974	SCV001423384	not provided	Ehlers-Danlos syndrome, type 4		no assertion provided	phenotyping only	Variant interpretted as Uncertain significance and reported on 02-03-2016 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.